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PubMed2001

Spectrum of floppy children in Indian scenario.

OBJECTIVE: To study the clinical profile of paralytic floppy infants undertaking available investigations and detect the frequency of exon7 of survival motor neuron (SMNT) gene deletion among the spinal muscular atrophy (SMA) cases. DESIGN: Descriptive study. SETTING: Tertiary care teaching hospital. SUBJECTS: 70 paralytic floppy infants (40 males/30 females) with age less than 13 years were included in the study. Exclusion criteria included central hypotonia of any cause. Detailed clinical evaluation was done followed by serum creatine phosphokinase levels, electrophysiological studies, muscle biopsy including immunohistochemistry and electron microscopy. Exon7 of SMNT gene deletion studies was done by PCR. RESULTS: Final diagnosis of SMA was assigned to 37 patients followed by congenital myopathy (n = 7), cogenital muscular dystrophy (n = 5), mitochondrial myopathy (n = 4), neuropathies (n = 5) and diaphragmatic SMA (n = 1). Only 15.7% of cases remained unclassified. When EMG was correlated with final diagnosis, it was 80.6% and 75% sensitive and 68.8% and 87.5% specific for neurogenic and muscle disease, respectively. Muscle biopsy revealed neurogenic atrophy in 47.8% cases followed by normal in 37.3% and myopathic pattern in 14.97% cases. Exon7 of SMNT gene was deleted in only 50% of SMA cases. CONCLUSIONS: Spinal muscular atrophy was the commonest cause of floppy children. The low rate of SMNT gene deletion detected needs confirmation with further studies.

Child↗
PubMed1996

[Motor neuron diseases: a type of programmed cell death?].

Motor neuron diseases in humans, which include amyotrophic lateral sclerosis (ALS) and spinal muscular atrophies (SMAs), are characterized by motorneuron loss and chromatolysis in some or many remaining cells of the anterior horn of the spinal cord. Motorneurons are filled with phosphorylated neurofilaments, and ubiquitinated filamentous and granular inclusions which conform Lewy-like bodies in ALS patients. In addition, axonal balloonings filled with phosphorylated neurofilaments are usually observed in ALS patients with predominant signs of spinal motor neuron deficits and rapid clinical course. SMAs also occur in other species. Loss of motorneurons and chromatolytic cells filled with phosphorylated neurofilaments are the main pathologic findings in the ventral horn. In both humans and animals, loss of synaptic afferents is found in chromatolytic cells but not in normally-appearing motorneurons, thus suggesting that loss of synapses is a later event in motor neuron disease. These morphological features, together with the lack of c-Jun/AP-1 immunostaining and lack of staining with the method of in situ labelling of nuclear DNA fragmentation of dying cells, are different from those found during the process of naturally occurring (programmed) cell death in normal development. Although deletions in the SMN and NAIP genes located in 5q are found in patients with SMA, the cell death programme in SMA should not be considered as a mere persistence or reactivation of naturally occurring (programmed) cell death during normal development.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Mutant androgen receptor accumulation in spinal and bulbar muscular atrophy scrotal skin: a pathogenic marker.

OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The nuclear accumulation of mutant AR is central to the pathogenesis of SBMA. Androgen deprivation with leuprorelin inhibits mutant AR accumulation, resulting in rescue of neuronal dysfunction in a mouse model of SBMA. This study aimed to investigate whether mutant AR accumulation in the scrotal skin is an appropriate biomarker of SBMA. METHODS: Immunohistochemistry of both scrotal skin and the spinal cord was performed on five autopsied SBMA cases. Neurological severity and scrotal skin findings were studied in another 13 patients. Five other patients received subcutaneous injections of leuprorelin and underwent scrotal skin biopsy. RESULTS: The degree of mutant AR accumulation in scrotal skin epithelial cells tended to be correlated with that in the spinal motor neurons in autopsy specimens, and it was well correlated with CAG repeat length and inversely correlated with the amyotrophic lateral sclerosis functional scale. Leuprorelin treatment inhibited mutant AR protein accumulation in the scrotal skin of SBMA patients. INTERPRETATION: These observations suggest that scrotal skin biopsy findings are a potent pathogenic marker of SBMA and can be a surrogate end point in therapeutic trials.

Adult↗
PubMed1993

Investigations on the occurrence of hereditary diseases in the Danish cattle population 1989-1991.

The methods of the Danish Bovine Genetic Disease Programme are outlined, and the results obtained during the first 3 years in function are described. The most common disease reported was spinal muscular atrophy in calves of the Red Danish Dairy breed with 312 reports. Necropsy was performed on 162 cases, and spinal muscular atrophy was diagnosed in 82 of these. Bovine progressive degenerative myeloencephalopathy, rectovaginal constriction, syndrome of arthrogryposis and palatoschisis, hereditary chondrodysplasia (2 different types), syndactylism, epitheliogenesis imperfecta, and osteogenesis imperfecta was diagnosed with 1 case each. Lethal trait A46 was diagnosed in 4 calves. Some of these diseases have not previously been described in Denmark, and epitheliogenesis imperfecta was for the first time diagnosed in the Hereford breed. Chromosome translocation 1/29 was detected in the Blonde d'Aquitaine (BAQ), Limousine, and Red Danish Dairy breed. The aberration occurred frequently in BAQ. Furthermore, a complex chromosome translocation t(1;8;9)(q45;q13;q26) was detected in the Red Danish Dairy breed.

Abnormalities, Multiple↗
PubMed1989

[Muscle fiber type abnormalities in bulbospinal muscular atrophy. Comparison with amyotrophic lateral sclerosis].

Bulbospinal muscular atrophy (BSA) is a distinct clinical type of chronic spinal muscular atrophy of adult onset, which was first reported by Kennedy et al. Histochemical findings of involved muscles are poorly described. In the present study, the muscle fiber type was studied on biopsied specimens by the histochemical method. The results were compared with those of amyotrophic lateral sclerosis (ALS). Muscle specimens were obtained mainly from biceps brachii muscles of 7 cases of BSA and 10 cases of ALS. Both group of patients were matched in respect to age, sex and stage of muscle weakness. The following results were obtained. Histopathological findings of BSA are classed as stage 4 abnormalities of Jennekins. Both fiber type grouping and type 2B deficiency are more frequent in BSA than in ALS. Type 2C fiber seems to be more in ALS than in BSA. Atrophy factor of Dubowitz is the same in BSA and in ALS. Hypertrophy factor is more prominent in BSA than in ALS. Significant correlation between fiber type grouping and type 2B deficiency was confirmed in muscles from other neurogenic atrophy. Since there is a significant association of the type 2B deficiency with fiber type grouping, type 2B fiber might be transformed to type 2A during the reinnervation process. The adaptation to the increased activities of the survived muscles and motoneurons might be contributory to the transformation, which is already known to occur in normal subjects during the endurance training.

Adult↗
PubMed1993

Discrimination between neuropathy and myopathy by use of magnetic resonance imaging.

Since discrimination between myopathy and neuropathy may be difficult it seemed reasonable to investigate the possibility of assessment of these disorders by means of magnetic resonance imaging. Children with Duchenne muscular dystrophy and children with the juvenile type of spinal muscular atrophy were selected for the study and compared to healthy volunteers. Measurements were performed on a small Bruker imaging system operating at 2.35 T, and T1 weighed images on the lower extremities were recorded. Images obtained on the diseased extremities could be clearly distinguished from the images from healthy children. Furthermore, preferential involvement of fast muscles in patients with muscular dystrophy, and differences in distribution of fatty degeneration of muscles enable reliable discrimination between muscular dystrophy and spinal muscular atrophy.

Adolescent↗
PubMed2001

Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy.

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons of the spinal cord associated with muscle paralysis and caused by mutations of the survival motor neuron gene (SMN). To determine whether SMN gene defect in skeletal muscle might have a role in SMA pathogenesis, deletion of murine SMN exon 7, the most frequent mutation found in SMA, has been restricted to skeletal muscle by using the Cre-loxP system. Mutant mice display ongoing muscle necrosis with a dystrophic phenotype leading to muscle paralysis and death. The dystrophic phenotype is associated with elevated levels of creatine kinase activity, Evans blue dye uptake into muscle fibers, reduced amount of dystrophin and upregulation of utrophin expression suggesting a destabilization of the sarcolemma components. The mutant mice will be a valuable model for elucidating the underlying mechanism. Moreover, our results suggest a primary involvement of skeletal muscle in human SMA, which may contribute to motor defect in addition to muscle denervation caused by the motor neuron degeneration. These data may have important implications for the development of therapeutic strategies in SMA.

Animals↗
PubMed2000

The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells.

The human neuronal apoptosis inhibitory protein (NAIP) gene has been discovered as a candidate gene for spinal muscular atrophy, a genetic disorder characterized by motor neuron loss in the spinal cord. The telomeric NAIP gene on human chromosome 5 is deleted together with survival motor neurons (SMN) in many cases of the most severe forms of the disorder. NAIP, c-IAP1 (inhibitor of apoptosis-1), c-IAP2, X-IAP, survivin and Apollon comprise the mammalian inhibitors of the apoptosis family and contain an N-terminal domain with 1-3 imperfect repeats of an approximately 65 amino acids domain named the baculovirus IAP repeat (BIR) motif. We identified six NAIP genes in the mouse genome which were found to be expressed in a broad range of tissues. Furthermore, we have investigated the effects of NAIP in the rat pheochromocytoma PC12 cell line. These cells differentiate in the presence of nerve growth factor (NGF) into cells that resemble sympathetic neurons. We observed that NAIP overexpression impaired NGF-induced neurite outgrowth. The BIR motifs of NAIP (residues 1-345) were not required for this effect. However, the BIR domains of NAIP were essential to prevent apoptosis in PC12 cells after NGF deprivation or TNF-alpha receptor stimulation. Expression of full-length but not BIR-deleted-NAIP protects against cell death. This correlates with reduced activity of the cell death effector protease, caspase-3, in lysates of NAIP-PC12 cells, as measured by cleavage of the fluorogenic tetrapeptide substrate Asp-Glu-Val-Asp. Thus, unregulation of cellular differentiation and/or caspase suppression may contribute to motoneuron dysfunction and cell death in spinal muscular atrophy where NAIP is mutated.

Amino Acid Motifs↗
PubMed1999

Clinical spectrum and diagnostic difficulties of infantile ponto-cerebellar hypoplasia type 1.

We present the clinical and histopathological features and the diagnostic difficulties encountered in five children affected by a motor neuron disorder other than spinal muscular atrophy. Investigations performed suggested the diagnosis of ponto-cerebellar hypoplasia type 1 (PCH-1). Severe respiratory difficulty was present at birth in two of these children; hypotonia, arthrogryposis, microcephaly and nystagmus were present in all. Early and progressive bulbar involvement with swallowing difficulties and stridor was also a common feature in these infants. Severe cognitive delay was invariably present. Brain magnetic resonance imaging showed ponto-cerebellar hypoplasia in four children while striking atrophy of the cerebellar vermis and cerebellar hemispheres were present in the fifth child. Electrophysiological and pathological investigations of proximal muscles performed at presentation in all these children were not conclusive, while the post-mortem studies, or the study of distal muscles during life, showed a clear neurogenic picture. Genetic studies excluded involvement of the SMN gene, or of other genes located on chromosome 5q, confirming that ponto-cerebellar hypoplasia type 1 is a different entity from typical proximal spinal muscular atrophy.

Abnormalities, Multiple↗
PubMed1984

Heart disease in myasthenia gravis.

Patients with myasthenia gravis (MG) may develop heart disease. Our data on 108 MG patients were examined to assess the type and frequency of this. 17 of 108 patients (16%) showed signs of heart disease which could be regarded as MG-related. 11 of these, of whom 5 died suddenly, had clinical symptoms, mainly arrhythmias. Signs of heart disease were most frequent in thymoma patients (5 of 10), and all 3 microscopically examined hearts from these patients showed a focal myocarditis. 44 spinal muscular atrophy patients serving as controls showed a 16% frequency of signs of heart disease of unknown etiology. However, only 1 of 44 spinal muscular atrophy patients (2%) had clinical symptoms as compared to 11 of 108 MG patients (10%). Together with the characteristic focal nature of the myocarditis and the microscopic similarities between lesions of heart and skeletal muscle, this indicates that the heart disease is specifically related to MG.

Adolescent↗
PubMed1981

[Progressive bulbar paralysis in childhood with pyramidal signs (author's transl)].

We report on a 8 year-old boy who presented with progressive bulbar paralysis. Remarkable were the presence of pyramidal signs, the visual disturbances, the peculiar gait and the intermittent progression of the disease. Our case supports the idea that spinal muscular atrophies form a group of diseases with variable expression. We can classify our patient between the juvenile form and the adult form of spinal muscular atrophy with progressive bulbar palsy. We could follow this boy for almost 4 years. He died at the age of twelve years. Post mortem examination was not permitted.

Bulbar Palsy, Progressive↗
PubMed1998

Caspase-3 cleaves the expanded androgen receptor protein of spinal and bulbar muscular atrophy in a polyglutamine repeat length-dependent manner.

Spinal and bulbar muscular atrophy (SBMA) is one of a group of human inherited neurodegenerative diseases caused by polyglutamine expansion. There is increasing evidence that generation of truncated proteins containing an expanded polyglutamine tract may be an important step in the pathogenesis of these disorders. We have previously demonstrated that the SBMA gene product, the androgen receptor (AR) protein, is toxic when truncated. We now report that in vitro translated full-length AR proteins containing different sized polyglutamine repeats (24, 65 and 97 repeats, respectively) are specifically cleaved by recombinant caspase-3, liberating a polyglutamine containing fragment, and that the susceptibility to cleavage is polyglutamine repeat length-dependent. These findings suggest that AR protein is one of the "death substrates" cleaved by caspase-3 and that caspase-3 might be involved in the pathogenesis of SBMA.

Bulbar Palsy, Progressive↗
PubMed2005

Age-dependent differences in androgen binding affinity in a family with spinal and bulbar muscular atrophy.

OBJECTIVES: To investigate androgen receptor (AR) function in spinal and bulbar muscular atrophy (SBMA). METHODS: A kindred was identified with five individuals carrying the AR gene CAG repeat expansion that causes SBMA. Androgen binding was measured in cultured genital skin fibroblasts from three affected individuals. One newborn, pre-symptomatic, individual showed normal androgen binding, but two older, symptomatic individuals showed a decrease in androgen binding affinity. This difference was not related to AR CAG repeat size, as all affected individuals in this kindred had 49 repeats (normal range 6-35). Post-mortem analysis in one subject confirmed the signs of androgen insufficiency in the testis, with marked seminiferous tubule atrophy, and the absence of germinal cells. The characteristic neuronal depletion in the anterior horn gray matter was also observed. CONCLUSION: This report raises the possibility that age- or puberty-related changes in androgen binding could occur, which could potentially contribute to the progressive development of androgen resistance in affected men.

Adult↗
PubMed2003

The myopathology of floppy and hypotonic infants in Singapore.

AIMS: This study attempts to determine the type and relative frequency of muscle diseases contributing to floppy and hypotonic infants in Singapore. METHODS: Eighty consecutive muscle biopsies in the Department of Pathology, National University of Singapore, in the period 1978-2000, in which a clinical diagnosis of floppy or hypotonic infant was made, were reviewed. RESULTS: The commonest cause of severe hypotonia in infancy was spinal muscular atrophy, which accounted for 33% of cases followed by congenital muscular dystrophy (13%). Eight cases (10%) of infantile type II glycogenosis (Pompe's disease) were encountered. There were seven cases of congenital myopathy, of which four were centronuclear myopathy, and one each of central core myopathy, nemaline myopathy and congenital fibre type disproportion. One case of centronuclear myopathy was associated with type I fibre smallness. Type II atrophy, which is generally considered a non-specific change, was encountered in five cases. Of interest is the relatively large number of muscle biopsies (29%) in which no significant pathological features were encountered at the light microscopic, histochemical as well as ultra-structural level. CONCLUSIONS: The study has revealed a great variety of pathology affecting the muscle of children presenting as floppy infants or with hypotonia. The muscle diseases included spinal muscular atrophy, congenital muscular dystrophies, congenital myopathies and metabolic myopathies. However, 23 (29%) cases showed no significant pathology. For this group of floppy and hypotonic infants further studies are needed.

China↗
PubMed1995

Expression of transforming growth factor-beta 1 in dystrophic patient muscles correlates with fibrosis. Pathogenetic role of a fibrogenic cytokine.

Duchenne muscular dystrophy is a fatal disorder characterized by progressive muscular weakness, wasting, and severe muscle contractures in later disease stages. Muscle biopsy reveals conspicuous myofiber degeneration and fibrosis substituting muscle tissue. We quantitatively determined mRNA of the potent fibrogenic cytokine transforming growth factor-beta 1 by quantitative PCR in 15 Duchenne muscular dystrophy, 13 Becker muscular dystrophy, 11 spinal muscular atrophy patients, and 16 controls. Higher transforming growth factor-beta 1 expression was greater in Duchenne muscular dystrophy patients than controls (P = 0.012) and Becker patients (P = 0.03). Fibrosis was significantly more prominent in Duchenne muscular dystrophy than Becker muscular dystrophy, spinal muscular atrophy, and controls. The proportion of connective tissue in muscle biopsies increased progressively with age in Duchenne muscular dystrophy patients, while transforming growth factor-beta 1 levels peaked at 2 and 6 yr of age. Transforming growth factor-beta 1 protein was also detected by immunocytochemistry and immunoblotting. Our findings suggest that transforming growth factor-beta 1 stimulates fibrosis in Duchenne muscular dystrophy. Expression of transforming growth factor-beta 1 in the early stages of Duchenne muscular dystrophy may be critical in initiating muscle fibrosis and antifibrosis treatment could slow progression of the disease, increasing the utility of gene therapy.

Age Factors↗